TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti–PD-1 in Lung Adenocarcinoma

Clinical Cancer Research - Tập 24 Số 22 - Trang 5710-5723 - 2018
Jérôme Biton1, Audrey Mansuet‐Lupo, Nicolas Pécuchet, Marco Alifano, Hanane Ouakrim, Jennifer Arrondeau, Pascaline Boudou‐Rouquette, François Goldwasser, Karen Leroy, Jérémy Goc, Marie Wislez, Claire Germain, Pierre Laurent‐Puig, Marie‐Caroline Dieu‐Nosjean, Isabelle Cremer, Ronald Herbst, Hélène Blons, Diane Damotte
1Centre de Recherche des Cordeliers

Tóm tắt

Abstract Purpose: By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non–small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. Experimental Design: We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained. Results: We showed that distinct combinations of STK11, EGFR, and TP53 mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16–0.63, P < 0.001) was observed in anti–PD-1-treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Conclusions: Our study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Clin Cancer Res; 24(22); 5710–23. ©2018 AACR.

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Clinical Cancer Research

Tập 24 Số 22

5710-5723

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